Targeting Metabolic Adaptive Responses to Chemotherapy

Abstract

Methods for targeting adaptive responses to chemotherapy are described. In various embodiments, a method comprises administering at least one compound that inhibits S6K1, mTORC1 or upstream or downstream pathway components of S6K1 or mTORC1, in association with administration of at least one inhibitor of PPARα, PPARδ, or PGC1α. In various embodiments, the compound that inhibits S6K1, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 is rapamycin, everolimus, temsirolimus, or imatinib. The inhibitor of PPARα, PPARδ, or PGC1α can be an antagonist or an inverse agonist selected from GW6471, GSK3787, GSK0660, and ST247.

What is claimed is: 
     
         1 . A method comprising administering at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1, in association with administration of at least one inhibitor of PPARα, PPARδ, or PGC1α, wherein said inhibitor of PPARα, PPARδ, or PGC1α is an antagonist or an inverse agonist of PPARα, PPARδ, or PGC1α. 
     
     
         2 . The method of  claim 1 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 comprises at least one compound that inhibits BCR-ABL. 
     
     
         3 . The method of  claim 1 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 is selected from the group consisting of rapamycin, everolimus, temsirolimus, Torin1, and BEZ235. 
     
     
         4 . The method of  claim 3 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 is rapamycin. 
     
     
         5 . The method of  claim 1 , wherein the at least one inhibitor of PPARα, PPARδ, or PGC1α is selected from the group consisting of GW6471, GSK3787, GSK0660, and ST247. 
     
     
         6 . The method of  claim 1 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 and the at least one inhibitor of PPARα, PPARδ, or PGC1α are administered concurrently. 
     
     
         7 . The method of  claim 1 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 and the at least one inhibitor of PPARα, PPARδ, or PGC1α are administered separately. 
     
     
         8 . The method of  claim 1 , wherein the at least one compound that inhibits S6K1, mTOR, mTORC1, or upstream or downstream pathway components of S6K1 or mTORC1 comprises at least one compound that inhibits S6K1, and wherein the at least one inhibitor of PPARα, PPARδ, or PGC1α comprises at least one inverse agonist of PPARδ. 
     
     
         9 . The method of  claim 8 , wherein the at least one compound that inhibits S6K1 and the at least one inverse agonist of PPARδ are administered concurrently. 
     
     
         11 . The method of  claim 8 , wherein the at least one compound that inhibits S6K1 and the at least one inverse agonist of PPARδ are administered separately. 
     
     
         12 . A method for treating cancer comprising administering a compound that inhibits at least one component of the mTOR pathway in association with an inhibitor of PPARα, PPARδ, or PGC1α. 
     
     
         13 . The method of  claim 12 , wherein the cancer is a leukemia. 
     
     
         14 . The method of  claim 13 , wherein the cancer is chronic myelogenous leukemia. 
     
     
         15 . The method of  claim 12 , wherein the compound that inhibits at least one component of the mTOR pathway comprises a compound that inhibits S6K1. 
     
     
         16 . The method of  claim 12 , wherein the compound that inhibits at least one component of the mTOR pathway is selected from a group consisting of rapamycin, everolimus, temsirolimus, Torin1, and BEZ235. 
     
     
         17 . A composition comprising:
 (a) a compound that inhibits at least one component of the mTOR pathway;   (b) a compound that inhibits PPARα, PPARδ, or PGC1α; and   (c) at least one carrier.   
     
     
         18 . The composition of  claim 17 , wherein the compound that inhibits at least one component of the mTOR pathway is selected from the group consisting of rapamycin, everolimus, temsirolimus, Torin1, and BEZ235 and the compound that inhibits PPARα, PPARδ, or PGC1α is ST247. 
     
     
         19 . The composition of  claim 17 , wherein the compound that inhibits PPARα, PPARδ, or PGC1α is ST247. 
     
     
         20 . A method of treating cancer comprising administering rapamycin or a rapalog in combination with ST247.